tbuckley/cabot-search huggingface dataset:
DIPG-13. NEW IMMUNOCOMPETENT GENETICALLY-ENGINEERED MOUSE MODELS OF PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMAS REVEAL MECHANISMS OF TUMOR INITIATION AND PROGRESSION
Authors: Ruxiao Tian, Annette Wu, Eric Laugesen, Tak Mak, Jerome Fortin
Journal: Neuro-Oncology (2023)

Abstract Pediatric-type diffuse high-grade gliomas (pHGGs) form a group of aggressive brain tumors with very poor prognosis. Recurrent driver mutations in TP53 and histone H3-encoding genes, most commonly H3F3A, are observed in a large proportion of these tumors. H3-K27M substitutions are particularly prevalent in midline gliomas, and H3-G34R mutations occur in supratentorial tumors. To better understand the molecular mechanisms driving pHGG emergence and progression, we set out to develop immunocompetent mouse models recapitulating the oncogenic lesions observed in human tumors. Given that oligodendrocyte progenitor cells (OPCs) may be the cells of origin of some pHGGs, we investigated the effect of mutation induction in the OLIG2-expressing cell lineage, using the Olig2Cre driver. Interestingly, deletion of the P53-encoding gene, Trp53, in Trp53flox/flox;Olig2Cre/+ mice led to the development of diffuse gliomas in nearly all animals. Latency to humane endpoint was relatively long (&amp;gt;1 year), and tumors developed throughout the brain with a mild preference for infratentorial (e.g. brainstem) localization. The gliomas diffusely infiltrated the brain parenchyma, and were heterogeneously immuno-reactive for OPC, astrocytic, and neural progenitor cell (NPC) markers. Based on RNA sequencing, the tumors segregated in two groups: one enriched in expression of OPC genes, and another with a prominent NPC-like signature. Whole exome sequencing revealed frequent Ccnd1 and Kras/Hras copy number gains in advanced tumors. To model additional oncogenic lesions, we generated knock-in mice in which the H3f3aK27M or the H3f3aG34R mutations can be induced in any cell type with Cre recombinase, and extinguished with Flp recombinase. These were combined with conditional Trp53 loss-of-function alleles in various cell lineages, and their effect on tumor initiation and progression was monitored. Collectively, our studies provide new reagents for accurate disease modeling of pHGG in mice, opening opportunities to better understand tumor initiation and progression at high resolution, and for pre-clinical therapeutic testing.
MDB-38. COMPUTATIONAL DRUG SENSITIVITY PREDICTS MEDULLOBLASTOMA SUBGROUP-SPECIFIC THERAPEUTICS
Authors: Anna Jermakowicz, Robert Suter, Luz Ruiz, Nagi Ayad
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Tumors are typically characterized as Group 3, Group 4, SHH, or WNT. Current standard-of-care includes surgery, radiation, and chemotherapy; however, treatment response and prognosis vary widely between subgroups. Additionally, surviving children frequently suffer from lifelong neurocognitive deficits. Therefore, novel therapeutic options are urgently needed. Despite extensive characterization of medulloblastoma tumors into four molecular subgroups, few subgroup specific therapies have advanced to the clinic. To address this, we have developed a novel platform called DrugSeq, which predicts drug sensitivities in patients and can stratify tumors by subgroup. DrugSeq also identifies key pharmacotranscriptomic differences between primary and recurrent tumors. We first calculated disease signatures for each patient by normalizing gene expression to low grade glioma samples from the posterior fossa. Using previously developed transcriptional consensus signatures (TCSs) that represent the affect that a drug has on the gene expression across a panel of cancer cell lines, we then calculated the discordance between each patient disease signature and drug TCS. Finally, using an ANOVA analysis we identified drugs which are predicted to differentially target each medulloblastoma subgroup. Among our top predicted anti-cancer compounds we found several kinase inhibitors, bromodomain inhibitors, and several psychiatric drugs with known brain penetrance. Additionally, we show distinct differences in drug sensitivity predictions between newly diagnosed and recurrent tumors, such as sensitivity to BET inhibition for recurrent Group 3 and Group 4 tumors despite no predicted sensitivity in the newly diagnosed tumors. Future studies with larger datasets may be able to further subdivide patients by age or molecular features within subgroups. Collectively, we show that DrugSeq may identify novel therapies and facilitate patient stratification in clinical trials, leading to more successful targeted medulloblastoma therapies.
BIOL-02. MODELING BRAIN TUMORS IN VIVO AND WITH HUMAN ORGANOIDS
Authors: Luca Tiberi
Journal: Neuro-Oncology (2023)

Abstract Brain tumors are a large and heterogeneous group of neoplasms that affect the central nervous system and include some of the deadliest cancers. Almost all the conventional and new treatments fail to hinder tumoral growth of the most malignant brain tumors. This is due to multiple factors, such as intra-tumor heterogeneity, the microenvironmental properties of the human brain, and the lack of reliable models to test new therapies. Therefore, creating faithful models for each tumor and discovering tailored treatments pose great challenges in the fight against brain cancer. We have recently developed a human IPSCs-derived organoid model of pediatric medulloblastoma and pediatric high-grade glioma. These models overcome the limitations of using animal models and pave the way to gaining unprecedented new knowledge into the development of brain cancer in a human system. Nevertheless, to fill the gap in the brain cancer field it will be crucial to use patient-derived tissues. To this aim, in the next years, we will develop patient-derived organoids (PDO) of pediatric brain tumors. These organoids recapitulate several features of the primary human tumors, such as intra-tumor heterogeneity and genomic alternation. The production of PDOs will allow us to generate important new knowledge, discover of potential drug targets, and small molecules that could be exploited in early-phase clinical trials, hopefully, to develop and validate new treatments. Interestingly, the possibility of using organoids directly generated from pediatric tumors will also pave the bases for personalized therapies.
Common and Distinct Genetic Architecture of Age at Diagnosis of Diabetes in South Indian and European Populations
Authors: Sundararajan Srinivasan, Samuel Liju, Natarajan Sathish, Moneeza K. Siddiqui, Ranjit Mohan Anjana, Ewan R. Pearson, Alexander S.F. Doney, Viswanathan Mohan, Venkatesan Radha, Colin N.A. Palmer
Journal: Diabetes Care (2023)

OBJECTIVE South Asians are diagnosed with type 2 diabetes (T2D) more than a decade earlier in life than seen in European populations. We hypothesized that studying the genomics of age of diagnosis in these populations may give insight into the earlier age diagnosis of T2D among individuals of South Asian descent. RESEARCH DESIGN AND METHODS We conducted a meta-analysis of genome-wide association studies (GWAS) of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and South Asian Indians. RESULTS We identified two signals near the TCF7L2 and CDKAL1 genes associated with age at the onset of T2D. The strongest genome-wide significant variants at chromosome 10q25.3 in TCF7L2 (rs7903146; P = 2.4 × 10−12, β = −0.436; SE 0.02) and chromosome 6p22.3 in CDKAL1 (rs9368219; P = 2.29 × 10−8; β = −0.053; SE 0.01) were directionally consistent across ethnic groups and present at similar frequencies; however, both loci harbored additional independent signals that were only present in the South Indian cohorts. A genome-wide signal was also obtained at chromosome 10q26.12 in WDR11 (rs3011366; P = 3.255 × 10−8; β = 1.44; SE 0.25), specifically in the South Indian cohorts. Heritability estimates for the age at diagnosis were much stronger in South Indians than Europeans, and a polygenic risk score constructed based on South Indian GWAS explained ∼2% trait variance. CONCLUSIONS Our findings provide a better understanding of ethnic differences in the age at diagnosis and indicate the potential importance of ethnic differences in the genetic architecture underpinning T2D.
ATRT-04. TARGETING THE COREST COMPLEX HELPS REPROGRAM AT/RT’S ABNORMAL EPIGENETIC LANDSCAPE TOWARD A DIFFERENTIATION PHENOTYPE
Authors: Anupa Geethadevi, Marianne Collard, Nikhil Vaidya, Tyler Findlay, Kristen Malebranche, Charles Eberhart, Eric Raabe, Philip Cole, Rhoda Alani, Jeffrey Rubens
Journal: Neuro-Oncology (2023)

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are deadly infantile brain tumors. Their aggressive phenotype results from a single recurring biallelic loss-of-function mutation in genes encoding components of the SWI/SNF chromatin-remodeling complex - mainly SMARCB1 and SMARCA4 in remaining tumors. Residual SWI/SNF activity continues to inhibit EZH2 methyltransferase except at promoter regions colocalized to REST, which associates with neuronal differentiation and tumor suppressor genes. At these sites, EZH2 increases repressive H3K27me3 marks, helping maintain AT/RT in a stem cell-like state, and driving its aggressive growth and therapy resistance. We study the consequences of disrupting SWI/SNF inhibition at sites of EZH2/REST co-localization to target AT/RT precisely. The repressive action of REST is carried out mainly by the CoREST complex, consisting of LSD1, HDAC1/2 and RCOR. Lentiviral knockdown of RCOR2 reversed AT/RT’s stem cell-like state and induced differentiation along the glial and neuronal lineage. A decrease in the H3K27Me3 further confirmed the absence of COREST complex assembly at these sites. We used a bifunctional LSD1 and HDAC1/2 inhibitor, Corin, to pharmacologically target the CoREST complex in AT/RT cells. Corin also induced neuronal differentiation in AT/RT with increased expression of neuronal differentiation markers and decreased expression of stem cell markers. Further, Corin reduced AT/RT cell viability and proliferation (p&amp;lt;0.05) and increased apoptosis (p&amp;lt;0.05). In mice bearing orthotopic CHLA06 tumors, convection-enhanced delivery of a single dose of Corin increased H3K27ac, demonstrating that Corin engaged its target in vivo and induced apoptosis (western blot, cPARP). These studies demonstrate that targeting the CoREST complex disrupts AT/RT epigenetic abnormalities, reversing their stem cell-like state, slowing tumor cell growth, and inducing apoptosis. Targeting the CoREST complex with Corin is a promising new strategy that may translate into the clinical setting to help improve AT/RT’s dismal survival.
ATRT-03. THE ORAL IRON-MIMETIC GALLIUM MALTOLATE INHIBITS ATRT IN VIVO – IMAGING AND HISTOLOGICAL CHARACTERIZATION
Authors: Mona Al-Gizawiy, Robert T Wujek, Casey J Zoss, Ryuma Tanaka, Shama P Mirza, Christopher R Chitambar, Kathleen M Schmainda
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive CNS tumor that is associated with poor outcome. This dire prognosis is due in part to its poor response to the limited treatment options available. Iron and iron proteins play a key role in the growth of many solid cancers, including brain tumors. Our published studies show that the ferrobiology of brain tumors can be exploited for therapeutic purposes. Here, we further demonstrate the inhibitory effects of oral gallium maltolate (GaM) in pediatric ATRT in vivo. METHODS Pediatric CHLA-266 ATRT cells were stereotactically implanted into the right striatum of male athymic rats. Advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison (as indicator of tumor growth rate). RESULTS In concordance with our previous in vitro work, in vivo ATRT xenografts were found to be highly sensitive to oral GaM. Median overall survival was 89 days in the control group and 170 days in the treatment group (p=0.011). GaM-treated xenograft tumors grew at a significantly slower rate than control tumors (p&amp;lt;0.0001). On MRI, untreated ATRT xenograft tumors, as their clinical counterparts, tended to localize near the ventricle and occasionally invade it. Histologically, xenograft tumors in our rat model recapitulated the histological features of human ATRT. A significant reduction in MIB-1% and mitotic index (p&amp;lt;0.001 and p&amp;lt;0.05, respectively) was seen in the treatment group. Transferrin receptor and H-ferritin expression in GaM-treated tumors illustrated cellular iron deprivation. CONCLUSION Monotherapy with GaM profoundly inhibited ATRT growth and prolonged survival in vivo.
OTHR-14. PROFILE &amp; OUTCOME OF BRAIN TUMORS IN THE YOUNG CHILDREN &amp;lt; 3YEARS OF AGE: EXPERIENCE FROM A TERTIARY CANCER CENTER IN INDIA
Authors: Priyakumari Thankamony, Manjusha Nair, Binitha Rajeswary, Guruprasad CS, Prasanth VR
Journal: Neuro-Oncology (2023)

Abstract During the 5 year period from 1st January 2009- 31st December 2013, 33 children&amp;lt; 3 years age presented with brain tumor (7.56 % of all brain tumors among in children aged 0-14 years) . 54.5% were boys. Vomiting(69.7%) ataxia(36%) &amp; head ache(24%) were the most common symptoms. Common histology included Medulloblastoma (36%) , Astrocytoma ( 21%) &amp; Ependymoma ( 18%).Others included ATRT, glioma, ganglioglioma, PNET, Pineoblastoma &amp; choroid plexus carcinoma. 63% were infratentorial &amp; 37% were supratentorial. 58% had gross total resection &amp; 36% had residual disease post surgery .64% of children received chemotherapy with baby brain protocol consisting of Inj VCR 0.06mg/kg IV - D1 &amp;Inj Cyclophosphamide 50mg/kg IV infusion D1 (Cycle A) alternating with Inj CDDP 4m/kg as IV infusion D1&amp;Inj Etoposide 6.5mg/kg IV infusion D1-3( Cycle B) as A – A – B Q3 weeks followed by definitive RT at completion of 3 years or earlier if they relapse on chemotherapy . At a median follow up of 34 months ( ( 2 mo- 106 mo ) 3 year RFS &amp; OS were 20% &amp; 56% respectively. OS was better for Ependymoma ( 100%) &amp; Astrocytoma (80%) compared to (56% )for Medulloblastoma.
SURG-04. INFLUENCE OF LOW-INTENSITY FOCUSED ULTRASOUND ON LOCOREGIONAL DRUG DELIVERY TO THE BRAIN
Authors: Brice Martin, Rafael Uribe, Madeline Larabee, Mihaela Stavarache, Nadia Dahmane, Michael Kaplitt, Mark Souweidane
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Efficient delivery of therapeutic drugs across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) tumors is a major challenge to the development of safe and efficacious therapies. Among the different approaches developed to circumvent these limitations to improve drug delivery to a target tissue, low-intensity focused-ultrasound (LIFU) is a particularly appealing strategy as it will transiently disrupt the blood-brain barrier. Locoregional (intrathecal [IT] and convection-enhanced delivery [CED]) are clinically relevant routes of drug delivery that bypass the BBB and avoid systemic exposure. These routes of administration are known to achieve otherwise unobtainable drug concentration in specified target tissue. However, it remains unknown how locoregional routes of delivery coupled with FUS could change the drug targeting and pharmacokinetics. METHODS In the present study, we quantitatively assessed how FUS coupled with IT, IV, or CED altered fluorescent dye (Dextran 2000kD) distribution and concentration in a predetermined neurotomical region in a naïve murine model. We then analyzed the pharmacokinetic effects of using FUS mediated BBB disruption coupled with CED by measuring the volume of distribution and time-dependent concentration of the dye. RESULTS Our results indicate that IV administration coupled with LIFU will successfully cause diffusion of dye into the pre-defined sonication targets. Alternatively, measurable dye in the sonication target was hardly detected when administered IT in comparison to IV delivery (VIT = 1.25mm3; VIV = 36.20mm3). In addition, our preliminary qualitative analysis suggests that LIFU coupled with CED shows shorter time of residence of the dye in the parenchyma when compared to CED alone. This suggests that increased BBB permeability from FUS leads to faster drug clearance. CONCLUSION Our results highlight the distributive and pharmacokinetic influence of FUS on various locoregional drug delivery routes.
IMMU-03. IDENTIFICATION OF GENETIC BIOMARKERS TO PREDICT RESPONSE TO HSV-1 G207 AND POLIO:RHINOVIRUS IMMUNOTHERAPY
Authors: Eric Thompson, Kyung-Don Kang, Hengshan Zhang, Michael Brown, Kevin Stevenson, Gregory Friedman
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The polio:rhinovirus chimera, PVSRIPO, and the herpes simplex virus, G207, are viral immunotherapies with promising results in Phase I trials of pediatric high-grade glioma (pHGG) and medulloblastoma. While some patients have durable responses, others have no benefit. The purpose of this study is to identify genes that putatively confer resistance to viral immunotherapy. METHODS A panel of medulloblastoma and pHGG cell lines were treated with either PVSRIPO or G207 and categorized into “sensitive” and “resistant” groups based viability. Flow cytometry was used to quantify cell receptor expression (CD111 for G207, CD155 for PVSRIPO). RNA sequencing was completed on treated resistant and sensitive cells. RESULTS D341 and D556 medulloblastoma had &amp;lt; 50% viability at 72h (G207) and 24h (PVSRIPO) and were categorized as sensitive; D283 and D324 were categorized as resistant. There was a correlation between CD111 expression and cell viability (Spearman r=0.71) but no correlation between CD155 and viability. The number of significantly differentially expressed (DE) genes (adjusted p≤0.05) was significantly higher in sensitive compared to resistant medulloblastoma, both for enriched (mean 666.4±614 vs. 454.6±377.4, P=0.0422) and depleted (826.9±645.5 vs. 449±367.8, P=0.0167) genes after treatment. There were few shared DE genes between cells treated with PVSRIPO and G207: GCLM, LANCL2, and RBM3 were enriched while ADAMTS1 and VEGFA were depleted. Likewise, there were few shared DE genes enriched between medulloblastoma and pHGG cell lines treated with G207: GPSM2, CHECK2, SEPTIN2, EIF4G2, GCLM, GDAP1, LANCL2, and PWP1. CONCLUSIONS Genetic analysis demonstrates minimal overlap in DE genes between the two viral immunotherapies. PVRIPO and G207 infection resulted in significantly more DE gene expression in sensitive vs. resistant cells. GCLM and LANCL2 are enriched by both PVSRIPO and G207 and in medulloblastoma and pHGG. These genes may serve as potential biomarkers in predicting response to viral immunotherapy.
Hemostatic matrix for treating intracollection bleeding after endoscopic ultrasound-guided drainage and endoscopic necrosectomy of walled-off pancreatic necrosis in a patient with cirrhosis
Authors: Giacomo Emanuele Maria Rizzo, Dario Ligresti, Lucio Carrozza, Salvatore Tammaro, Mario Traina, Ilaria Tarantino
Journal: Endoscopy (2023)

A 45-year-old man with alcoholic liver cirrhosis was referred to our institute for treatment of infected walled-off pancreatic necrosis (WOPN) 6 months after an episode of acute pancreatitis. Computed tomography confirmed cirrhotic liver disease with collateral vessels and a pancreatic fluid collection at the body-tail (9 × 3 cm). Laboratory tests showed low platelets (55 000/mm3) and international normalized ratio of 1.5. Endoscopic ultrasound (EUS) evaluation showed perigastric collateral circulation and a WOPN with necrotic material accounting for 90 % of the total volume ([Fig. 1]).
MDB-07. MYC AND TGFΒ PROMOTE GROUP 3 MEDULLOBLASTOMA TUMOR RESISTANCE THROUGH DEREGULATION OF KDM2B TARGETS
Authors: Zulekha Qadeer, Samantha Westelman, Mackenzie Johnson, Shane Grele, Elise Hou, Liam Hendrikse, Linyu Wang, Sarah Husain, Mary Clare Beytagh, Christin Schmidt, Miller Huang, Michael Taylor, William Weiss
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at &amp;lt;50%, few recurrent mutations, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some MB tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We hypothesize that the TGFβ pathway and MYC contribute to the intrinsic resistance of G3MB through deregulation of key genes and pathways. We previously established humanized models for SHHMB by introducing MYCN or PTCH1 deletions into neuroepithelial stem cells (NESC) derived from normal human induced pluripotent stem cells (hIPSCs). In this study, we transduced NESCs with TGFb effectors activated in G3MB alone and/or in combination with MYC, prioritizing combinations observed in patients. Excitingly, both MYC and TGFβ effectors drove tumor formation in vivo with the combination of TGFβ effectors with MYC leading to more aggressive tumors. We next found that NESCs expressing MYC with either TGFβR1 or TGFβ1 showed resistance to clinical TGFβR1 inhibitors, compared to cells driven by either TGFβR1 or TGFβ1 alone. To decipher mechanisms of resistance, we integrated CUT&amp;RUN to probe for MYC genomic localization and relevant histone PTMs with RNA-seq analysis and discovered a subset of genes upregulated in MYC and TGFb-driven lines that are targets of the histone demethylase KDM2B. Loss of function mutations in KDM2B occur in G3MB patients, indicating that KDM2B deregulated genes are critical in G3MB. We postulate that epigenetic remodeling via MYC and recruitment of other MYC-interacting cofactors to KDM2B targets culminates in transcriptional changes that lead to aggressive disease. Overall, our studies provide important insight on identifying new therapeutic avenues for patients with MYC and TGFβ driven G3MB.
IMMU-14. WAKING THE SLEEPING GIANT: TLR7/8 AGONIST TREATMENT STIMULATES TUMOR-ASSOCIATED MYELOID CELLS FOR MEDULLOBLASTOMA IMMUNOTHERAPY
Authors: Coral Alicea Pauneto, Duhyeong Hwang, Daniel Malawsky, Kyoungtea Kim, Christopher Park, Marina Sokolsky, Timothy Gershon
Journal: Neuro-Oncology (2023)

Abstract Medulloblastomas contain large myeloid populations and we have identified a novel therapy that effectively recruits these non-tumor cells for anti-cancer effect. Medulloblastoma myeloid cells have bivalent functions, supporting tumor growth through IGF1 secretion and immunosuppression, or inhibiting tumor growth through diverse mechanisms including phagocytosis. We investigated a nanoparticle formulation of the TLR7/8 agonist Resiquimod (POx-Resiquimod), administered to Gfap-Cre/SmoM2 (G-Smo) mice that are engineered to develop SHH medulloblastomas, using animal survival time studies, flow cytometry and single-cell trancriptomics (scRNA-seq). POx-Resiquimod treatment increased the survival of G-Smo mice as a single agent and sensitized the typically radiation-resistant G-Smo tumors to radiation therapy. Mechanistically, POx-resiquimod increased the proportions of myeloid cells in medulloblastoma, while blocking IGF1 secretion and re-polarizing the myeloid population from anti-inflammatory to pro-inflammatory. POx-resiquimod induced phagocytosis-related genes, including CD72 and the scavenger receptor MARCO. Functional studies confirmed that POx-resiquidmod increased tumor cell phagocytosis, linking molecular changes to changes in myeloid cell behavior. Our data show that the innate immune function of myeloid cells can be harnessed for medulloblastoma treatment and identify the nanoparticle-delivered TLR7/8 agonist POx-Resiquimod as a specific and effective new agent for medulloblastoma immunotherapy that can be combined with existing modalities.